Opioid Combination: Rationale and Possible Clinical Applications

Review Article

Opioid combination: rationale and possible clinical applications

Sebastiano Mercadante

Anesthesia and Intensive Care and Pain Relief and Palliative Care, Via san Lorenzo 312, 90146 Palermo, Italy Corresponding to: Sebastiano Mercadante, MD. Anesthesia and Intensive Care and Pain Relief and Palliative Care, Via San Lorenzo 312, 90146 Palermo, Italy. Email: [email protected] or [email protected].

Abstract: The aim of this review is to provide a potential benefit of an opioid combination at receptor sites, based on experimental data and preliminary clinical studies where a combination of opioids with different characteristics yielded greater analgesic activity with lesser adverse effects. The receptor activity, including intrinsic activity, endocytosis, and oligomerization, and the interaction on opioid receptors and between different opioid receptors or different sites are described. Finally, clinical observations of opioid combinations reported in literature regarding the possible benefits of such an approach are presented.

Keywords: Opioid combination; cancer pain; chronic pain; tolerance; opioid receptor

Submitted Sep 03, 2013. Accepted for publication Sep 17, 2013. doi: 10.3978/j.issn.2224-5820.2013.09.04 Scan to your mobile device or view this article at: http://www.amepc.org/apm/article/view/2771/3723

Opioids are the mainstay of chronic cancer management implying that all µ opioids may not be working through the and are used for the treatment of moderate to severe same mechanism of action (3). Many observations suggest pain. The analgesic responses to analgesics, including the presence of functional interactions among µ opioid opioids, depend on a multitude of factors characterized by analgesics, consistent with the involvement of multiple a large intraindividual and interindividual variability (1). subpopulations of µ opioid receptors (4). Interactions with Drug-related and patient-related factors are the most other opioid receptors have also been recently reported. It relevant. Long-term clinical use of opioids (mainly µ agonists) has been shown in animal studies that when a µ-receptor can cause a wide range of adverse effects such as respiratory agonist (i.e., morphine) is co-administered with a δ-receptor depression, constipation, and tolerance. Tolerance to antagonist (i.e., naltrindole), then increased analgesia results different opioid effects develops at varying rates and accrues with an improved side-effect profile. Collectively, these data gradually with repeated dosing. Antinociceptive tolerance is indicate the potential of synergic effects when using opioids well documented and is characterized by a marked reduction with different receptor characteristics (5). Finally, potent in the pain-relieving effects of an opioid after repeated interactions between selected combinations of opioids and administration. Tolerance leads to dose escalation with NSAIDs have been demonstrated (6). the potential to increase intrinsic opioid toxicity, including The aim of this review is first to provide a potential opioid-induced hyperalgesia, which limits the tolerability of benefit of an opioid combination at receptor sites, based on an opioid treatment. experimental data and research suggesting possible clinical It has long been appreciated by clinicians that individual implications. Secondly, to provide information about patients may respond better to one µ-opioid than another, preliminary clinical studies where a combination of opioids improving tolerability and restoring satisfactory pain with different characteristics yielded greater analgesic relief. These findings suggest between-opioid differences, activity with lesser adverse effects. indicating a far more complex pharmacology for opioid receptors than it has previously been suggested (2). Opioid receptor activity Pharmacological differences among µ opioid drugs have been observed in vitro and in vivo preclinical models, Opioids act through more than one µ-receptors. Opioid

© AME Publishing Company. All rights reserved. www.amepc.org/apm Ann Palliat Med 2013;2(4):189-196 190 Mercadante. Opioid combination: rationale and clinical applications receptors are currently classified as µ, δ, and κ, with a Fentanyl, methadone, and etomorphine showed a greater fourth related non-classical opioid receptor for nociceptin/ receptor reserve than do morphine, levorphanol, and orphanin FQ. Opioids have overlapping selectivities at µ, δ, meperidine (12,13). Thus, the extent of tolerance to the and κ receptors as well as overlapping distribution patterns analgesic effects of µ-opioid agonists has been found to in the nervous system and differentially modulate a broad vary with the intrinsic activities of both of drug used to range of physiological functions (7). Opioids are commonly induce the tolerance and the drug being tested for analgesic classified by their selectivity and affinity in receptor binding activity (12). The latter hypothesis also has been tested studies. Opioid receptors belong to the large superfamily in relation to the dose-response changes with progressive of G-protein-coupled receptors. Opioid receptors act via increases in stimulus intensity (14,15). Several opioids, G-proteins to inhibit adenyl-cyclase, increase potassium including methadone, fentanyl and sufentanil have been currents, inhibit calcium channel activity, modulate inositol demonstrated to have much higher efficacy than morphine, triphosphate turnover, and activate mitogen-activated due to a higher receptor reserve than morphine (10,16), protein kinase. These actions culminate in the attenuation of possibly also due to their greater ability to induce receptor neuronal activity by inhibiting neurotransmitter release and internalization. When acting through the same receptor, changing neuronal excitability. However, despite apparent morphine, with its lower reserve, may lose its effectiveness similarities, many µ-opioid analgesics have interesting as a result of tolerance, acting as a partial agonist when pharmacological differences. µ-opioids are the most common compared to methadone (17). drugs used for analgesic purposes, and morphine is prototype With an increase in stimulus intensity, opioids with of this class of drugs. Most genes are composed by multiple a high efficacy showed less shift in their dose response exons that must be spliced together to generate the mRNA curves than an agonist with low efficacy (like morphine), that in turn produces the µ-receptor. Variability or mutation that shows a greater reduction in the maximum effect of these sequences may provide the ability of a single gene to and increased occupancy requirements. The greater shift generate a wide range or related proteins (8). The regulation in morphine dose-response relative to sufentanil when of the splicing is even more complex, dependent on the cell stimulus intensity rises may support the receptor occupancy (for example, spinal cord or other sites), and localization (for theory. Thus, whereas morphine acts as a full agonist at example pre or post-synaptically) (9). low stimulus intensity, it may become a partial agonist at The binding pocket of these variants, however, is high levels of pain stimulation, and the relative potency of identical, showing high affinity and selectivity for µ-opioids. sufentanil to morphine increases as tolerance develops (14). However, the number of receptors needed to be activated Although significant cross-tolerance for both sufentanil and in order to suppress neuronal activity differs significantly. morphine has been demonstrated, the magnitude of cross- Receptor conformation changes as a result of opioid binding tolerance from sufentanil to morphine was greater than and subsequently determines the efficacy of receptor from morphine to sufentanil, showing an asymmetrical activation and G-protein interactions. cross-tolerance (17). The level of antinociception produced by an opioid seems to be dependent on the intrinsic efficacy of the drug and the stimulus intensity. Interestingly, the Intrinsic activity level of antinociception produce by an opioid “per se” and Receptor occupancy and drug effect are directly related not necessarily the opioid intrinsic efficacy, may determines to the number of spare receptors. According to the law of the type of interaction among opioids (18). mass action, more potent drugs modify relatively fewer receptor-effector mechanisms to produce an effect. It has Endocytosis been suggested that the degree of tolerance is inversely related to the reserve of spare opioid receptors (10). Endocytosis has a well-established role in the desensitization Different drugs may produce equivalent pain relief while and downregulation of receptor-mediated signaling, occupying different proportions of the available receptors both of which have been implicated in the development (i.e., having different fractional receptor occupancies). of tolerance. The ability of selected opioid analgesics to As morphine has high occupancy characteristics, it is mediate regulation of receptor signaling by rapid endocytosis considered a low intrinsic efficacy agonist, and may induce represents an independent functional property that tolerance more readily than a high efficacy agonist (11). distinguishes clinically important opioid analgesics such

© AME Publishing Company. All rights reserved. www.amepc.org/apm Ann Palliat Med 2013;2(4):189-196 Annals of Palliative Medicine, Vol 2, No 4 October 2013 191 as morphine and methadone. Following activation, opioid of a μ-opioid reflect the summation of the activation of all receptors are regulated by multiple mechanisms, including the μ-opioid receptor. Although the μ-opioids generally a well-characterized and highly conserved process involving show similar binding affinities for most of the different receptor phosphorylation by G-protein coupled receptor opioid receptor variants, their ability to activate the various kinase a subsequent arrestin recruitment. These processes can receptor subtypes differs. The pharmacological effect of each contribute to desensitization by facilitating the uncoupling splice variant may vary from drug to drug depending upon of receptor from G protein. Following this desensitization, its potency and efficacy at that particular site (3). Opioid receptors are often endocytosed into an intracellular receptors undergo adaptations such as desensitization, compartment, from which they can be recycled to the down-regulation, and internalization in response to repeated membrane, leading to receptor downregulation. According administration of an agonist, each of these phenomena to this theory endocytosis serves a protective role in reducing contributing to the development of tolerance that the development of tolerance. This property profoundly undermines the use of opioids as analgesics (22). affects the regulation of downstream signaling and can be Opioid receptors are endocytosed by a mechanism distinguished both pharmacologically and mutationally from involving receptor phosphorilation, interaction with other important functional parameters such as potency and β-arrestin and then sequestered internally. Trafficking of intrinsic activity for receptor activation. The downstream G-protein-coupled receptor by rapid recycling pathway regulatory responses induced by the failure of morphine restores the complement of functional receptor and process to promote efficient arrestin-mediated desensitization may resensitization of receptor mediated signal transduction (23). include additional modifications of the receptor itself that The regulation of opioid receptors by endocytosis has change the apparent functional receptor reserve independent been hypothesized to have protective functions in reducing from changes in total receptor number (19). the development of tolerance. Agonist activity and receptor endocytosis have opposing effects on receptor-mediated signalling, and the final result is a function of both processes Oligomerization (named RAVE). Morphine, in comparison with other Receptors are coupled with a G-protein composed of three opioids has a high activity-endocytosis ratio, and has an units. When the complex is activated, GDP in the complex enhanced propensity to prolonging signals with prolonged unit of G-protein is replaced by GTP and leads to the drug exposure (24). The amount of internalization caused transduction of the signal. The receptor associated with by an agonist generally correlates with coupling efficiency. G-protein is tightly complexed by a number of proteins, Molecular events, such as desensitization and endocytosis producing a larger size of the solubilized µ-receptor would reduce this response. It has been experimentally complex (7). The ability of the receptors to dimerize and demonstrated that endocytosis-promoting agonists may their association with G-proteins, due to the different facilitate morphine-induced receptor endocytosis, reducing variants, define the type of transduction and the response. the compensatory adaptive cellular changes that lead to Thus, dimerization is a means by which G protein can cross upregulation of the cAMP pathway (25). Coadministration talk and amplify signals (20). Studies have confirmed that of DAMGO or fentanyl promoted morphine-induced opioid receptors not only dimerized in various combinations µ-receptor internalization. The analgesic effect of morphine but mostly exist as receptor dimers and not monomers was greatly potentiated when µ-receptor internalization in different tissues. Dimerization may modulate receptor was induced by coadministration of subanalgesic doses function (21). Heterotypic dimers have different opioid of DAMGO or fentanyl. In contrast, the combination of binding affinities, intrinsic efficacy, and receptor trafficking DAMGO and fentanyl increased neither the analgesic than monomers. In this way, different receptors, localized in effect not the internalization of µ-receptor (26). Thus, a different places, centrally or peripherally, all bind the same combination of opioids with different characteristics may drugs, but may produce a different effect, leading to either reciprocally alter their RAVEs, so reducing the potential for positive or negatively cooperativity (7). the development of tolerance. On the other hand, morphine treatment can produce adaptational changes which can attenuate high efficacy agonist-mediated desensitization and Interactions on μ-receptors internalization of G-protein-coupled receptors (27). The μ-opioid system is extremely complicated. The actions Functional interactions among µ opioid analgesics have

© AME Publishing Company. All rights reserved. www.amepc.org/apm Ann Palliat Med 2013;2(4):189-196 192 Mercadante. Opioid combination: rationale and clinical applications been demonstrated. Synergy between methadone and a to suggest that blocking δ-receptor while activating µ number of other µ-opioids have been found, also revealing produces antinociception without the development of incomplete cross-tolerance (28). The combination of tolerance (5). methadone with morphine offers a number of potential Functional interactions among opioid receptor types, not advantages, particularly since these interactions seem to always bidirectional, have been demonstrated. The repeated be restricted to analgesia, as inhibition of gastrointestinal stimulation of κ-opioid receptor markedly increased the transit is not increased. Moreover this effect was not functional µ and δ-opioid receptor, whereas repeated attributed to an interaction with NMDA receptors (4). stimulation of either µ- and δ-receptor had no direct effect Not all µ-analgesics have revealed synergy when given on κ-opioidergic function in mice (37). in combination. Only additive interactions between Morphine and oxycodone appear to exert their methadone and fentanyl or between morphine and M6G, antinociceptive actions via different classes of opioid have been found. receptors (24,28,38,39). In contrast to morphine, intrinsic antinociceptive effects of oxycodone seem to be principally mediated by putative κ-receptors (40). These findings Interactions between different opioid receptors could explain the asymmetric tolerance existing between or different sites oxycodone and morphine, minimally balanced by oxycodone Synergy is a commonplace in opioid pharmacology. The metabolites with µ-activity (28). Co-administration of interactions between opioid receptors have been the subject sub-antinociceptive doses of oxycodone and morphine of recent research. It has been postulated existence of produces marked antinociceptive synergy with reduced functional interactions between opioid receptors (29). It CNS side effects (24). In other experiments, repeated has been shown for morphine given both supraspinally and stimulation of κ-opioid receptors lead to the heterologous spinally underlining the importance of regional interactions upregulation of µ-opioid receptor functions which was either between different places in CNS and/or periphery associated with the supersensitivity of µ-opioid receptor (30,31), the route of administration having per se an effect mediated antinociception (40). κ-opioid receptor agonists on the degree of synergy (28,32). In animals rendered have been found to be particularly effective analgesics in tolerant to systemic morphine, a lack of tolerance to experimental models of visceral pain, acting peripherally intracerebrally administered morphine was found. Similarly (41,42). In a multimodal, tissue-differentiated experimental highly lipophilic µ-agonists, for example methadone given pain models in humans’ oxycodone showed a superior peripherally, show no analgesic cross tolerance in animals analgesic effect to morphine in visceral pain, but a similar treated by morphine, suggesting that changes in the ability analgesia in pain modulation of the skin and muscles (43). to cross the blood-brain barrier or other dispositional This differentiated effect has been attributed to the changes may be involved in the differential tolerance peripheral κ-agonist activity of oxycodone (44). development (33). The effects of oxycodone and morphine are modulated The fact that opioids can act with multiple receptor differently in experimental models of bone cancer pain. The activities and with site-dependent receptor profiles has µ opioid receptor activation by oxycodone in brain regions encouraged research to explore the interactions among related to pain signaling was attenuated less as compared different receptors. Although each opioid receptor can with the effects of morphine, suggesting that modification mediate its effect independently, a growing body of of the µ opioid receptor is responsible for the distinct evidence has been accumulating for the existence of cellular analgesic effect of oxycodone and morphine (45). or molecular interaction among opioid receptor types. In an early study alternating µ and δ receptor activations modified Clinical observations of opioid combinations the development of tolerance (34). Although the stimulation of µ, δ, and κ-receptors produces distinct pharmacological These findings raise the possibility of potential clinical effects, a possible co-localization in the same synapse advantages of combining several different opioids in pain may cause a substantial interaction between them, or a management. Clinical studies were based on the rationale combination of effects on different receptors result in a offered by several experimental investigations (38). The synergic effect. Synergy has been demonstrated between µ basic premise of an analgesic combination is that the two and δ opioids (35,36). There is some experimental evidence drugs operate through different mechanisms of action, so

© AME Publishing Company. All rights reserved. www.amepc.org/apm Ann Palliat Med 2013;2(4):189-196 Annals of Palliative Medicine, Vol 2, No 4 October 2013 193 the combination may result in a reduction in dose-related in patients with pain syndrome with a poor response to the adverse effects. Although anecdotally multiple opioids are previous opioid, regardless of the combination used. often simultaneously administered for different reasons, there are few trials assessing this specific topic. However, in Spinal morphine and systemic buprenorphine an historical control study of opioid rotation and hydration, 35% of the opioid rotations were partial because of practical The combination of spinal morphine and systemic problems (46). buprenorphine might be of clinical value because these opioids may interact at different levels, due to their differences in receptor activity. The antagonist effects Oxycodone-morphine combination have been reported only when high doses exceeding Whereas morphine is the prototypical m-opioid agonists, the therapeutic dose ranges were combined (52). The behavioral antinociceptive and cross-tolerance studies concurrent administration of spinal morphine and systemic indicated that pain-relieving effects of oxycodone are mediated buprenorphine produces an antinociceptive effect that by putative κ-opioid receptors, and an isobolographic analysis was greater than what could have been predicted from revealed marked antinociceptive synergy between these two individual dose-response curves. The blockade of κ-receptor drugs (24). These suggestive findings were supported by a by systemic buprenorphine has been hypothesized to clinical study of cancer patients which showed a 38% less play a role in providing superadditive analgesia with consumption of extra-doses of morphine in patients who spinal morphine (53). In recent studies, buprenorphine were administered oxycodone rather than morphine (47). might interact with mechanisms of hyperalgesia limiting In a subsequent study the improvement in the analgesic descending facilitation mediated by spinal dynorphine effect with the drug combination was not associated with expression by its κ-receptor antagonistic properties (54). disproportionate concomitant adverse effects such as ventilatory depression (48). However, in an experimental cold Transdermal fentanyl and other opioids pain study morphine and oxycodone did not produce synergic antinociceptive effects in healthy humans (49), although this Tramadol, which is a weak opioid which acts through both model was found questionable to predict clinically relevant monoaminergic and opioid mechanisms, has been used doses of opioids (50). to facilitate dose adjustment of transdermal fentanyl in a randomized controlled study of advanced cancer patients with pain. Pain control was achieved with much slower Multiple combinations dose escalation of fentanyl in comparison with patients The rapid need to escalate opioid doses is challenging for receiving conventional increasing doses of fentanyl. Thus physicians and represents a critical phase for patients who a combination of a strong opioid with a weak opioid to have poor pain control despite receiving progressively treat severe cancer pain allowed a more gradual increase increasing doses of opioids. The administration of small of analgesic dosing than was possible using transdermal doses of a second opioid in patients with an unfavourable fentanyl alone (55). response during escalation with the prior opioid has been The opioid combination of transdermal fentanyl and found effective in a preliminary report where oral morphine, oral morphine has been reported in a cancer patient. The transdermal fentanyl, and oral methadone were added to conversion from 300 μg/h of transdermal fentanyl to transdermal fentanyl, oral morphine, and oral morphine, 150 μg/h and 360 mg of oral morphine provides effective respectively. Lower increases of equivalent doses of the pain control and disappearance of neuroexcitatory adverse second opioid, less than 20%, provided a better analgesia. effects. The partial opioid rotation and opioid combination Global opioid escalation index calculated in the following were considered beneficial (56). weeks after starting the treatment, was maintained at levels considered as acceptable, about 5 on average. Of interest, Conclusions the relatively low doses of the second opioid administered did not produce adverse effects of significant intensity, The contribution of opioid receptor regulatory mechanisms while improving the analgesia (51). Thus, the second opioid to the development of tolerance, and as a consequence a added on the first one was able to brake opioid escalation reduction of clinical analgesia, is still not clarified. To a

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Cite this article as: Mercadante S. Opioid combination: rationale and possible clinical applications. Ann Palliat Med 2013;2(4):189-196. doi: 10.3978/j.issn.2224-5820.2013.09.04